Field of the Invention
The present invention relates to a novel heterocyclic sulfonamide compound having a Transient Receptor Potential Ankyrin 1 (TRPA1) antagonist activity and a pharmaceutical composition containing the compound, as well as a medicament useful for the prophylaxis and/or treatment of a disease involving TRPA1.
Discussion of the Background
Transient Receptor Potential Ankyrin 1 (TRPA1) is a non-selective cation channel belonging to the Transient Receptor Potential (TRP) channel superfamily. Like other TRP channel family, it has 6 transmembrane domains and forms a tetramer consisting of 4 subunits. TRPA1 is a ligand-gated ion channel, which changes structure by the binding of ligand. As a result, the channel opens to allow intracellular flow of cations such as calcium ion, sodium ion and the like, thereby controlling the membrane potential of the cells. As the TRPA1 ligand, irritating natural substances (e.g., allylisothiocyanate (AITC), cinnamaldehyde and the like), environmental irritants (e.g., formalin, acrolein and the like), endogenous substances (e.g., 4-hydroxynonenal and the like) and the like are known (non-patent documents 1-3). It is known that the ligand is also activated by cold stimulation, intracellular Ca2+ and the like (non-patent document 1). Many ligands such as AITC, cinnamaldehyde and the like form a covalent bond with the cysteine residue and the lysine residue at the N-terminus in the cytoplasm, and activate the channel (non-patent document 2). In addition, intracellular Ca2+ is considered to bind to the N-terminus EF hand domain and opens the channel (non-patent document 4). TRPA1 has been reported to be highly expressed in the sensory nerves such as spinal cord nerve, vagus nerve, trigeminal nerve and the like. Also, TRPA1 has been reported to be co-expressed with TRPV1, perception⋅pain-related markers such as calcitonin gene related peptide (CGRP), substance P and the like (non-patent documents 5-7). Therefore, it is considered that, once TRPA1 in the sensory nerve is activated by various stimulations, channel opening and depolarization of the cellular membrane occur, neuropeptides (CGRP, substance P) are released from the nerve ending, and perception such as nociception and the like is transmitted.
In fact, it has been reported that TRPA1 gene knockdown by the gene specific antisense method improves hyperalgesia induced by inflammation and nerve damage in pain model (non-patent document 8). Also, it has been reported that a pain behavior induced by formalin is ablated in TRPA1 gene knockout mouse (non-patent document 9). From the above, TRPA1 is considered to play an important role in the nociceptive transmission. Involvement of TRPA1 in migraine and diabetic neuropathy is suggested in reports (non-patent documents 10, 11), and TRPA1 is also expected as a therapeutic target in pain-related diseases such as nociceptive pain, neuropathic pain and the like.
Also, TRPA1 is known to be highly expressed in the afferent sensory nerve projected on the gastrointestinal tract such as esophagus, stomach, large intestine and the like. It has been reported that TRPA1 knockdown decreases pain reaction through stomach extension (non-patent document 12), and colon hyperalgesia induced by AITC and 2,4,6-trinitrobenzenesulfonic acid (TNBS) are normalized in TRPA1 gene knockout mouse (non-patent document 13). From the above, TRPA1 is suggested to play an important role in the transmission of perception and nociception in the gastrointestinal tract, and is expected to be effective for the treatment of digestive tract diseases such as functional dyspepsia, irritable bowel syndrome, reflux esophagitis, inflammatory bowel disease (Crohn's disease, ulcerative colitis), pancreatitis (non-patent document 14) and the like.
Furthermore, TRPA1 plays a key role in the detection of a noxious substance in the trachea. It has been reported that TRPA1 gene knockout suppresses inflammation of the trachea in OVA model (non-patent document 15). Therefore, antagonism of TRPA1 is considered to be also useful for pulmonary diseases such as asthma, chronic coughing, chronic obstructive pulmonary disease (COPD) and the like.
As other diseases involving TRPA1, dermatic diseases such as pruritus, allergic dermatitis including atopic dermatitis, burn and the like (non-patent documents 16, 17, 18, 19), inflammatory diseases such as burn, osteoarthritis and the like (non-patent document 20), bladder diseases such as overactive bladder, abnormal urination, cystitis and the like (non-patent document 21), neurological diseases such as anticancer agent-induced neuropathy and the like (non-patent documents 22-24) and the like are known. Thus, a compound capable of regulating function of TRPA1 is industrially and therapeutically useful in many aspects. In particular, a compound that antagonizes TRPA1 is highly expected as a new therapeutic drug for pain diseases, digestive tract diseases, lung diseases, dermatic diseases, inflammatory diseases, bladder diseases and neurological diseases in human.
As a TRPA1 antagonist, a compound of the following formula has been reported (patent document 1).
wherein definition of each symbol is as described in patent document 1.
However, these compounds are structurally different from the compound represented by the formula (I) to be mentioned later. While patent document 3 also reports them as TRPA1 antagonists, they are structurally different from the compound represented by the formula (I) of the present invention to be mentioned later.
In addition, a compound having the following structure is known (patent document 2).
wherein definition of each symbol is as described in patent document 2.
However, these compounds are VLA-4 and α4β7 antagonists and have different action mechanism from that of the compound of the present invention. In addition, they have an alkyl group substituted by carboxylic acid or carboxylic acid as a substituent on the carbon atom adjacent to an amide bond, and are structurally different from the compound of the present invention.